ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1765G>A (p.Asp589Asn) (rs201971888)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237292 SCV000295644 uncertain significance Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237292 SCV000503409 uncertain significance Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / in association with c.769C>T, p.Arg257Trp/Software predictions: Benign
Invitae RCV000775077 SCV000544660 uncertain significance Familial hypercholesterolemia 2018-08-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 589 of the LDLR protein (p.Asp589Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs201971888, ExAC 0.08%). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 16250003, 25962062, 22353362, 20538126, 26343872, 27206935, 29399563, 28502495). This variant is also known as p.Asp568Asn in the literature. This variant is reportedly found on the same allele as LDLR p.Arg257Trp (PMID: 16250003, 18325082). ClinVar contains an entry for this variant (Variation ID: 252022). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Robarts Research Institute,Western University RCV000237292 SCV000782927 uncertain significance Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Color RCV000775077 SCV000909179 uncertain significance Familial hypercholesterolemia 2018-05-15 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant (also known as p.Asp568Asn in the mature protein) is a missense variant located in the LDLR class B (YWTD) repeat 5 of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia in Korea, Taiwan and the Netherlands (PMID 16250003, 25962062, 22353362, 20538126, 26343872). This variant has also been identified in 18/246268 chromosomes (17/17248 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845536 SCV000987650 uncertain significance not provided criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237292 SCV000606508 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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